Autoantibodies to Insulin Receptor Spontaneously Develop as Anti-Idiotypes in Mice Immunized with Insulin

Shechter, Yoram; Maron, Ruth; Elias, Dana; Cohen, Irun R.

doi:10.1126/science.7041258

Cited by 164 publications

(45 citation statements)

References 31 publications

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“…Our findings also exclude the possibility that the observed cross-reactivity is caused by the spontaneous development of anti-idiotypic antibodies, a phenomenon quite common for receptors and their ligands and first reported by Sege and Peterson (39) for the insulin-insulin receptor system. This observation later was confirmed by demonstrating that mice immunized with bovine insulin spontaneously developed anti-insulin receptor antibodies that exerted an insulin-like effect (40,41).…”

Section: Fig 7 Western Blot Analysis Of Recombinant Fragments Of Rapmentioning

confidence: 51%

Receptor-associated Protein and Members of the Low Density Lipoprotein Receptor Family Share a Common Epitope

Hiesberger

Hodits

Ullrich

et al. 1996

Journal of Biological Chemistry

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Receptor-associated-protein (RAP) 1 was initially described as a 39 -40-kDa protein copurifying with LDL receptor (LDLR)-related protein (LRP) (1, 2). At the same time, a putative target antigen in Heymann nephritis (HN), an experimental rat model of human membranous nephropathy, was identified and cloned (3). On molecular characterization of RAP, it became evident that the protein identified as the target antigen in HN was identical to RAP and not, as previously assumed, a fragment of glycoprotein 330/megalin (4). RAP subsequently was shown to bind not only to LRP but also to other members of the LDLR family, including megalin (5), the VLDLR (6), the chicken oocyte receptor for VLDL and vitellogenin (LR8) (7,8) and, to a lesser extent, to the LDLR itself (8, 9). The ability to interfere with ligand binding to these receptors has made RAP a perfect tool to study ligand-receptor interaction both in vitro (8, 10 -14) and in vivo (15). The latter experiments especially have established the role of LRP as a chylomicron remnant receptor in the liver. Despite the successful use of RAP to study the physiological function(s) of members of the LDLR family and of LRP in particular, clues about the function of RAP in vivo emerged only recently. The tetrapeptide sequence HNEL at the carboxyl terminus of RAP was shown to be necessary for the retention of RAP in the endoplasmic reticulum; thus, RAP associates in vivo with LRP early in the secretory pathway and dissociates from the receptor before reaching the cell surface (16). These results suggested a specialized role of RAP as a chaperon for LRP, possibly regulating the interaction of the receptor with ligands along the secretory pathway. This was confirmed by elegant studies by Herz and colleagues in RAP knockout mice (17) and in cultured cells in experiments relating the biosynthesis and functional expression of LRP and megalin with that of RAP (18). These experiments show that at least one of the physiological functions of RAP can be defined as that of a specialized escort protein, which protects certain receptors from ligand-induced aggregation along their intracellular itinerary. We have previously shown that LR8 can serve as a model system to study ligand binding and structural aspects of LDLR family members (8,19,20). Here we have used LR8 to demonstrate that all receptors that strongly bind RAP share a common immunological epitope with the escort protein. Based on this observation, we propose a model for the development of passive Heymann nephritis induced by anti-RAP antibodies, in which megalin present in the brush borders of the proximal kidney tubule in rats constitutes an additional target antigen. EXPERIMENTAL PROCEDURESPreparation and Radiolabeling of Ligands-VLDL was prepared from plasma of estrogen-treated roosters by sequential ultracentrifugation according to the method of George et al. (21). VLDL was labeled with 125 I to a specific activity of 250 -400 cpm/ng using the iodine

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Section: Fig 7 Western Blot Analysis Of Recombinant Fragments Of Rapmentioning

confidence: 51%

Receptor-associated Protein and Members of the Low Density Lipoprotein Receptor Family Share a Common Epitope

Hiesberger

Hodits

Ullrich

et al. 1996

Journal of Biological Chemistry

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“…Potential advantages of an antibody-free state include freedom from lipoatrophy and allergic phenomena, decreased insulin dose, predictability of insulin absorption, preservation of endogenous secretion of insulin, and possible avoidance of the generation of anti-idiotypic antibodies [17]. Older studies, however, using recrystallized pancreatic human insulin cast some doubt upon the possibility that injected homologous insulin can be made non-immunogenic [18].…”

Section: Discussionmentioning

confidence: 99%

Immunogenicity of recombinant DNA human insulin

et al. 1983

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“…Anti-idiotypic antibodies with internal image activity have been demonstrated in several antigenic systems. For example, polyclonal rabbit anti-idiotypic antibodies raised against antibodies to the physiologic ligands, such as insulin (5,6), retinol binding protein (5), and alprenolol (7), were able to bind the cellular receptors of these ligands. The detection of anti-idiotypic antibodies in the sera of patients with autoimmune disorders such as type B insulin-resistant diabetes, Graves disease, and myasthenia gravis has also helped to explain the presence of receptor-binding immunoglobulins in these sera (8)(9)(10).…”

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confidence: 99%

Nucleic acid sequence of an internal image-bearing monoclonal anti-idiotype and its comparison to the sequence of the external antigen.

Bruck¹,

Co²,

Slaoui³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

149

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The monoclonal anti-idiotypic antibody (mAb2) 87.92.6 directed against the 9B.G5 antibody specific for the virus neutralizing epitope on the mammalian reovirus type 3 hemagglutinin was previously demonstrated to express an internal image of the receptor binding epitope of the reovirus type 3. Furthermore, this mAb2 has autoimmune reactivity to the cell surface receptor of the reovirus. The nucleotide and deduced amino acid sequences of the 87.92.6 mAb2 heavy and light chains are described in this report. The sequence analysis reveals that the same heavy chain variable and joining (VH and JH) gene segments are used by the 87.92.6 anti-idiotypic mAb2 and by the dominant idiotypes of the BALB/c anti-GAT (cGAT) and anti-NP (NP3) responses. [GAT; random polymer that is 60% glutamic acid, 30% alanine, and 10% tyrosine. NP; (4-hydroxy-3-nitrophenyl)-acetyl.] Despite extensive homology at the level of the heavy chain variable regions, the NP3 positive BALB/c anti-NP monoclonal antibody 17.2.25 binds neither 9B.G5 nor the cellular receptor for the hemagglutinin. Amino acid sequence comparison between the viral hemagglutinin and the 87.92.6 mAb2 light chain "internal image," reveals an area of significant homology indicating that antigen mimicry by antibodies may be achieved by sharing primary structure.

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Autoantibodies to Insulin Receptor Spontaneously Develop as Anti-Idiotypes in Mice Immunized with Insulin

Cited by 164 publications

References 31 publications

Receptor-associated Protein and Members of the Low Density Lipoprotein Receptor Family Share a Common Epitope

Receptor-associated Protein and Members of the Low Density Lipoprotein Receptor Family Share a Common Epitope

Immunogenicity of recombinant DNA human insulin

Nucleic acid sequence of an internal image-bearing monoclonal anti-idiotype and its comparison to the sequence of the external antigen.

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